Serine/threonine-protein kinase Chk1

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Reviewed, UniProtKB/Swiss-Prot O14757 (CHK1_HUMAN)

Last modified June 10, 2008. Version 97. History...

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Names and origin · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Serine/threonine-protein kinase Chk1
Also known as:
EC 2.7.11.1

Gene names

Name:	CHEK1
Synonyms:	CHK1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein existence

Evidence at protein level.

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General annotation (Comments)

Function	Required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Inhibition of CDC25 activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Binds to and phosphorylates RAD51 at 'Thr-309', which may enhance the association of RAD51 with chromatin and promote DNA repair by homologous recombination. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may affect chromatin assembly during S phase or DNA repair. May also phosphorylate multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and enhances suppression of cellular proliferation.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Subunit structure	Interacts with BRCA1, CLSPN, PPM1D, RAD51, TIMELESS, XPO1/CRM1 and YWHAZ/14-3-3 zeta.
Subcellular location	Nucleus. Cytoplasm. Note=Nuclear export is mediated at least in part by XPO1/CRM1. Also localizes to the centrosome specifically during interphase, where it may protect centrosomal CDC2 kinase from inappropriate activation by cytoplasmic CDC25B.
Tissue specificity	Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon.
Domain	The autoinhibitory region (AIR) inhibits the activity of the kinase domain.
Post-translational modification	Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. May also be phosphorylated at Ser-280 by AKT1/PKB, which may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, which results in decreased activity. Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily. Contains 1 protein kinase domain.

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Ontologies

Keywords
Biological process	Cell cycle DNA damage DNA repair
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	DNA damage checkpoint Ref.1 Traceable author statement. Source: ProtInc DNA replication Inferred from Experiment. Source: Reactome gamete generation Ref.2 Traceable author statement. Source: ProtInc meiotic recombination Ref.1 Traceable author statement. Source: ProtInc negative regulation of cell proliferation Ref.1 Traceable author statement. Source: ProtInc regulation of cyclin-dependent protein kinase activity Ref.1 Traceable author statement. Source: ProtInc
Cellular component	condensed nuclear chromosome Ref.2 Traceable author statement. Source: ProtInc nucleoplasm Ref.15 Inferred from Experiment. Source: Reactome
Molecular function	protein binding Inferred from physical interaction. Source: IntAct protein serine/threonine kinase activity Inferred from Experiment. Source: Reactome
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct
AATF	Q9NY61	1	EBI-974488,EBI-372428
CDC25A	P30304	1	EBI-974488,EBI-747671
CDC25C	P30307	1	EBI-974488,EBI-974439
CLSPN	Q9HAW4	4	EBI-974488,EBI-1369377
HSP90AB1	P08238	1	EBI-974488,EBI-352572

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 476

476

Serine/threonine-protein kinase Chk1

Regions

Domain

9 – 265

257

Protein kinase

Nucleotide binding

15 – 23

ATP By similarity

Region

391 – 476

Autoinhibitory region

Sites

Active site

130

Proton acceptor

Binding site

ATP By similarity

Amino acid modifications

Modified residue

280

Phosphoserine; by PKB/AKT1 By similarity

Modified residue

296

Phosphoserine

Modified residue

308

Phosphoserine

Modified residue

317

Phosphoserine; by ATM and ATR

Modified residue

345

Phosphoserine; by ATM and ATR

Cross-link

436

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Natural variations

Natural variant

156

R → Q: dbSNP rs3731410.

Natural variant

Natural variant

Natural variant

V → I: dbSNP rs506504.

Experimental info

Mutagenesis

K → R: Abolishes kinase activity

Mutagenesis

130

D → A: Abolishes kinase activity

Mutagenesis

317

S → A: Abrogates interaction with RAD51; when associated with A-345. Reduces phosphorylation and impairs activation by hydroxyurea and ionizing radiation. Abrogates nuclear retention upon checkpoint activation

Mutagenesis

317

S → E: Enhances interaction with RAD51; when associated with E-345

Mutagenesis

344

F → A: Impairs nuclear export

Mutagenesis

345

S → A: Abrogates interaction with RAD51; when associated with A-317. Reduces phosphorylation and impairs activation by hydroxyurea and ionizing radiation. Impairs interaction with YWHAZ which is required for nuclear retention after checkpoint activation

Mutagenesis

345

S → E: Enhances interaction with RAD51; when associated with E-317

Mutagenesis

353

M → A: Impairs nuclear export

Mutagenesis

357

S → A: No effect on phosphorylation induced by hydroxyurea

Mutagenesis

366

S → A: No effect on phosphorylation induced by hydroxyurea

Mutagenesis

468

S → A: No effect on phosphorylation induced by hydroxyurea

Secondary structure

476

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

O14757-1 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: 0ABD0FAB67F49F67
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FASTA

476

54,420

        10         20         30         40         50         60 
MAVPFVEDWD LVQTLGEGAY GEVQLAVNRV TEEAVAVKIV DMKRAVDCPE NIKKEICINK 

        70         80         90        100        110        120 
MLNHENVVKF YGHRREGNIQ YLFLEYCSGG ELFDRIEPDI GMPEPDAQRF FHQLMAGVVY 

       130        140        150        160        170        180 
LHGIGITHRD IKPENLLLDE RDNLKISDFG LATVFRYNNR ERLLNKMCGT LPYVAPELLK 

       190        200        210        220        230        240 
RREFHAEPVD VWSCGIVLTA MLAGELPWDQ PSDSCQEYSD WKEKKTYLNP WKKIDSAPLA 

       250        260        270        280        290        300 
LLHKILVENP SARITIPDIK KDRWYNKPLK KGAKRPRVTS GGVSESPSGF SKHIQSNLDF 

       310        320        330        340        350        360 
SPVNSASSEE NVKYSSSQPE PRTGLSLWDT SPSYIDKLVQ GISFSQPTCP DHMLLNSQLL 

       370        380        390        400        410        420 
GTPGSSQNPW QRLVKRMTRF FTKLDADKSY QCLKETCEKL GYQWKKSCMN QVTISTTDRR 

       430        440        450        460        470 
NNKLIFKVNL LEMDDKILVD FRLSKGDGLE FKRHFLKIKG KLIDIVSSQK VWLPAT

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25." Sanchez Y., Wong C., Thoma R.S., Richman R., Wu Z., Piwnica-Worms H., Elledge S.J. Science 277:1497-1501(1997) [PubMed: 9278511] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH CDC25A; CDC25B AND CDC25C, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, PHOSPHORYLATION, MUTAGENESIS OF ASP-130.
[2]	"Atm-dependent interactions of a mammalian chk1 homolog with meiotic chromosomes." Flaggs G., Plug A.W., Dunks K.M., Mundt K.E., Ford J.C., Quiggle M.R.E., Taylor E.M., Westphal C.H., Ashley T., Hoekstra M.F., Carr A.M. Curr. Biol. 7:977-986(1997) [PubMed: 9382850] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Analysis of the candidate target genes for mutation in microsatellite instability-positive cancers of the colorectum, stomach, and endometrium." Semba S., Ouyang H., Han S.-Y., Kato Y., Horii A. Int. J. Oncol. 16:731-737(2000) [PubMed: 10717241] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Rieder M.J., Livingston R.J., Braun A.C., Montoya M.A., Chung M.-W., Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A. Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLN-156.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Bone marrow and Muscle.
[6]	"The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites." Shieh S.-Y., Ahn J., Tamai K., Taya Y., Prives C. Genes Dev. 14:289-300(2000) [PubMed: 10673501] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ASP-130.
[7]	Erratum Shieh S.-Y., Ahn J., Tamai K., Taya Y., Prives C. Genes Dev. 14:750-750(2000)
[8]	"Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint." Liu Q., Guntuku S., Cui X.-S., Matsuoka S., Cortez D., Tamai K., Luo G., Carattini-Rivera S., DeMayo F., Bradley A., Donehower L.A., Elledge S.J. Genes Dev. 14:1448-1459(2000) [PubMed: 10859164] [Abstract] Cited for: PHOSPHORYLATION AT SER-345.
[9]	"Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing." Feijoo C., Hall-Jackson C., Wu R., Jenkins D., Leitch J., Gilbert D.M., Smythe C. J. Cell Biol. 154:913-923(2001) [PubMed: 11535615] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION BY ATR, MUTAGENESIS OF ASP-130.
[10]	"ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1." Zhao H., Piwnica-Worms H. Mol. Cell. Biol. 21:4129-4139(2001) [PubMed: 11390642] [Abstract] Cited for: PHOSPHORYLATION AT SER-317 AND SER-345, MUTAGENESIS OF ASP-130; SER-317; SER-345; SER-357; SER-366 AND SER-468.
[11]	"Determination of substrate motifs for human Chk1 and hCds1/Chk2 by the oriented peptide library approach." O'Neill T., Giarratani L., Chen P., Iyer L., Lee C.-H., Bobiak M., Kanai F., Zhou B.-B., Chung J.H., Rathbun G.A. J. Biol. Chem. 277:16102-16115(2002) [PubMed: 11821419] [Abstract] Cited for: SUBSTRATE SPECIFICITY, MUTAGENESIS OF ASP-130.
[12]	Erratum O'Neill T., Giarratani L., Chen P., Iyer L., Lee C.-H., Bobiak M., Kanai F., Zhou B.-B., Chung J.H., Rathbun G.A. J. Biol. Chem. 277:35776-35777(2002)
[13]	"An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage." Heffernan T.P., Simpson D.A., Frank A.R., Heinloth A.N., Paules R.S., Cordeiro-Stone M., Kaufmann W.K. Mol. Cell. Biol. 22:8552-8561(2002) [PubMed: 12446774] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-317 AND SER-345, MUTAGENESIS OF LYS-38.
[14]	"BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage." Yarden R.I., Pardo-Reoyo S., Sgagias M., Cowan K.H., Brody L.C. Nat. Genet. 30:285-289(2002) [PubMed: 11836499] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH BRCA1.
[15]	"Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints." Zhao H., Watkins J.L., Piwnica-Worms H. Proc. Natl. Acad. Sci. U.S.A. 99:14795-14800(2002) [PubMed: 12399544] [Abstract] Cited for: FUNCTION.
[16]	"Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A." Soerensen C.S., Syljuaesen R.G., Falck J., Schroeder T., Roennstrand L., Khanna K.K., Zhou B.-B., Bartek J., Lukas J. Cancer Cell 3:247-258(2003) [PubMed: 12676583] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-317 AND SER-345, MUTAGENESIS OF SER-317 AND SER-345.
[17]	"Human tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint." Groth A., Lukas J., Nigg E.A., Sillje H.H.W., Wernstedt C., Bartek J., Hansen K. EMBO J. 22:1676-1687(2003) [PubMed: 12660173] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-317.
[18]	"SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase." Jin J., Shirogane T., Xu L., Nalepa G., Qin J., Elledge S.J., Harper J.W. Genes Dev. 17:3062-3074(2003) [PubMed: 14681206] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ASP-130.
[19]	"Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on ser-317 in response to ionizing radiation." Gatei M., Sloper K., Soerensen C., Syljuaesen R., Falck J., Hobson K., Savage K., Lukas J., Zhou B.-B., Bartek J., Khanna K.K. J. Biol. Chem. 278:14806-14811(2003) [PubMed: 12588868] [Abstract] Cited for: PHOSPHORYLATION AT SER-317, MUTAGENESIS OF ASP-130; SER-317 AND SER-345.
[20]	"Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents." Xiao Z., Chen Z., Gunasekera A.H., Sowin T.J., Rosenberg S.H., Fesik S., Zhang H. J. Biol. Chem. 278:21767-21773(2003) [PubMed: 12676925] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-345.
[21]	"Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on ser-345." Jiang K., Pereira E., Maxfield M., Russell B., Goudelock D.M., Sanchez Y. J. Biol. Chem. 278:25207-25217(2003) [PubMed: 12676962] [Abstract] Cited for: INTERACTION WITH YWHAZ AND XPO1, SUBCELLULAR LOCATION, ASSOCIATION WITH CHROMATIN, PHOSPHORYLATION AT SER-317 AND SER-345, MUTAGENESIS OF SER-317; PHE-344; SER-345 AND MET-353.
[22]	"Phosphorylation at serine 75 is required for UV-mediated degradation of human Cdc25A phosphatase at the S-phase checkpoint." Hassepass I., Voit R., Hoffmann I. J. Biol. Chem. 278:29824-29829(2003) [PubMed: 12759351] [Abstract] Cited for: FUNCTION.
[23]	"Human claspin is required for replication checkpoint control." Chini C.C.S., Chen J. J. Biol. Chem. 278:30057-30062(2003) [PubMed: 12766152] [Abstract] Cited for: INTERACTION WITH CLSPN.
[24]	"Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding." Chen M.-S., Ryan C.E., Piwnica-Worms H. Mol. Cell. Biol. 23:7488-7497(2003) [PubMed: 14559997] [Abstract] Cited for: FUNCTION.
[25]	"Suppression of tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1." Krause D.R., Jonnalagadda J.C., Gatei M.H., Sillje H.H.W., Zhou B.-B., Nigg E.A., Khanna K. Oncogene 22:5927-5937(2003) [PubMed: 12955071] [Abstract] Cited for: FUNCTION.
[26]	"MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation." Wang Y., Qin J. Proc. Natl. Acad. Sci. U.S.A. 100:15387-15392(2003) [PubMed: 14657349] [Abstract] Cited for: PHOSPHORYLATION AT SER-317.
[27]	"The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways." Pichierri P., Rosselli F. EMBO J. 23:1178-1187(2004) [PubMed: 14988723] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-345.
[28]	"Differential mode of regulation of the checkpoint kinases CHK1 and CHK2 by their regulatory domains." Ng C.-P., Lee H.C., Ho C.W., Arooz T., Siu W.Y., Lau A., Poon R.Y.C. J. Biol. Chem. 279:8808-8819(2004) [PubMed: 14681223] [Abstract] Cited for: DOMAIN, MITOTIC PHOSPHORYLATION, PHOSPHORYLATION AT SER-345, MUTAGENESIS OF LYS-38.
[29]	"Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase." Kraemer A., Mailand N., Lukas C., Syljuaesen R.G., Wilkinson C.J., Nigg E.A., Bartek J., Lukas J. Nat. Cell Biol. 6:884-891(2004) [PubMed: 15311285] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-130.
[30]	"DNA-dependent phosphorylation of Chk1 and claspin in a human cell-free system." Clarke C.A.L., Clarke P.R. Biochem. J. 388:705-712(2005) [PubMed: 15707391] [Abstract] Cited for: INTERACTION WITH CLSPN, PHOSPHORYLATION AT SER-296; SER-317 AND SER-345.
[31]	"Lack of PTEN sequesters CHK1 and initiates genetic instability." Puc J., Keniry M., Li H.S.,

Names and origin

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Secondary structure

Sequences

References